5alpha, 10beta-dihalo estranes and process therefor



United States Patent O 3,139,446 cc,10fi-DIHALO ESTRANES AND PRQCESS THEREFQR Albert Bowers, Mexico City, Mexico, assignor, by mesnc assignments, to Syntax Corporation, a corporation of Panama No Drawing. Filed May 2, 1961, Seto No. 107,050 17 Claims. (Cl. 260-6974;)

The present invention relates to novel cyclopentanophenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to 5,10- dihaloestrane derivatives.

The novel compounds of the present invention are represented by the following formulas:

In the above formulae, A represents the carbonyl the p-hydroxymethylene group OH (V or the fi-hydrocarbon carboxylic acyloxymethylene group X represents bromine, chlorine or iodine; Y represents chlorine, bromine or fluorine; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 car bon atoms; R represents hydrogen or an alkyl group containing up to 8 carbon atoms such as methyl, ethyl, propyl, n-butyl and the like. When R represents hydrogen, R represents solely a hydrocarbon carboxylic acyl group. R represents an alkenyl or alkynyl group containing up to 12 carbon atoms such as ethenyl, propen(1)yl, buten(3)- yl, ethynyl, propyn(l)yl, propen(2)y1, butyn(2)yl and the like.

The acyl groups are derived from hydrocarbon carboxylic acids of less than twelve carbon atoms, saturated or unsaturated, of straight, branched, cyclic or cyclicaliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 8 carbon atoms, amino, nitro or halogen. Typical ester groups are the acetate, propionate, butyrate, benzoate, cyclopentylpropionate, aminoacetate, ,B-chloropropionate, hemisuccinate, enanthate, caproate, trimethylacetate, methoxyacetate, phenoxyacetate, and phenylpropionate.

The compounds represented by the above Formula I are therapeutic agents usable in known manner both orally and by injection, for agents having androgenic and anabolic activities with a favorable anabolic-androgenic ratio. These compounds alsohave anti-gonadotropic and antiestrogenic activities, inhibit the secretion of the pituitar V gland and lower the blood cholesterol level.

and inhibit ovulation. These are also usable in conventional oral manner or by the way of injection. These compounds also have anti-estrogenic, anti-androgenic and anti-gonadotropic activity, inhibit the secretion of the pituitary gland and lower the blood cholesterol level.

The novel compounds of the present invention may be prepared by a process illustrated by the following equation:

on GR p g 0 V o: I 7 HO;

7 III IV X (W X In the above formulae, X, Y and R have the same meaning as previously set forth, R represents hydrogen or an alkyl or alkynyl group containing up to 12 carbon atoms and R represents an alkenyl group containing up to 12 carbon atoms.

In practicing the process outlined above, the starting compound, 17,8 acetoxy A estren 3 one (III) [Djerassi et al., I. Am. Chem. Soc. 78, 6362 (1956)] is reduced with a metal hydride preferably sodium borohydride in a suitable solvent such as methanol giving 17/3- acetoxy-A -estren-3B-ol (IV).

Treatment of this compound with a halogenating agent in a suitable solvent such as bromine in carbon tetrachloride yields 50;,10/3 dibromo 17/3 acetoxy estran- 3 6-01 (V:X= Y=bromine) The halogenating agent may also be a halogen halide as for example bromine fluoride in which case the agent is generated in situ from an N-halo-amide in this case N- bromoacetamide and the corresponding hydrogen halide, in this case hydrogen fluoride, and the reaction is conducted at very low temperature as for example C.,

thus affording: 5a fluoro 106 bromo 17/3 acetoxyestran-B/i-ol (V:X=bromine; Y=fiuorine). When this sequence of reactions is applied to a 17a-alkynyl-estrane derivative such as z17a-ethynyl-A estren 17,8 ol- 3-one (F. B. Colton, US. Patent 2,725,389) utilising as the halogenating agent for example bromine in carbon tetrachloride, there is obtained 5u,10fi dibrorno L- ethynyl-estrane 3,8,17/8 diol which upon hydrogenation in the presence of a suitable catalyst such as palladium on calcium carbonate aflords the corresponding 17a-alkenyl derivative which in this case is SaJOB-dibromQ-I'I-aethenyl-estrane-3/8,l7fl-diol (V11).

Upon oxidation of the above-mentioned lip-alcohols such as 5a,IOB-dibromo-17B-acetoxy-estran-3B-ol or See, 10fl-dibromo-l7a-ethenyl-estrane-3B,17/3-diol with, for example, 8 N chromic acid, there are obtained the corresponding 3-ketone derivatives, in this case 5a,10,8 dibromo-17l3-acetoxy-estran-3-one (VI) or 5a,10B-dibromo-l7a-ethenyl-estran-l7fl-ol-3-one (VIII).

Upon acylation of a l7fl-alcohol derivative selected from the above obtained compounds such as 5a,l0fi-dibromo-l7a-ethynyl-estrane-3fl,17B-diol in the presence of p-toluenesulfonic acid with an acylating agent as for example acetic anhydride, there is obtained the corresponding diester, in this case the 36,17fi-diacetate of 5a,10,B-dibromo-l7a-ethynyl-estrane-3fi,l7fi-diol. A 3-ketone such as 5 a,10/3-dibromo-17 OL-fithGHYI-ESII'BII-17fi-O1-3-Onfl affords the corresponding 17,8-monoester, in this case the 17fi-acetate of 5a,1OB-dibromo-17a-ethenyl-estran-17fi-ol-3-one.

Acylation of a 3,8,175-diol derivative as for example 5a,10,8-dibromo-17a-methyl-estrane-3B,17B-diol in the absence of p-toluenesulfonic acid affords the corresponding 3/8-monoester, in this case the 3B-acetate of 50:,10B-dlbromo-17a-methyl-estran-3fi,17fi-diol.

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I 1 g. of l7p-acetoxy-A estren-B-one [Djerassi et al., J. Am. Chem. Soc. 78, 6362 (1956)] was suspended in 120 cc. of methanol and treated at C. with a solution of 350 mg. of sodium borohydride in 1 cc. of water. The mixture was kept overnight at room temperature. The excess reagent was decomposed by addition of acetic acid and the resulting solution was concentrated under vacuum to a small volume. Water was added and the product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue was recrystallized from acetone-methylene chloride, thus furnishing l7fl-acetoxy-A -estren-3 13-01.

To a solution of 0.75 g. of the foregoing steroid in 40 cc. of carbon tetrachloride there was added dropwise a solution of bromine in the same solvent containing 1.1 molar equivalents of bromine. The operation was conducted under constant stirring and at room temperature. The resulting mixture was kept at the same temperature for thirty minutes, then poured into a 5% sodium bicarbonate aqueous solution and more carbon tetrachloride was added for the extraction of the product. The extract was subsequently washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded SaJOB-dibmmo-Uflacetoxy-estran-3 ,B-ol.

Example II Using exactly the same conditions described in Example I except that the bromine solution was substituted by a chlorine solution there was obtained 5a,l0fl-dichlorol7fi-acetoxy-estran-3B-ol.

Example III 750 mg. of 17,8-acetoxy-A -estren-3B-ol obtained according to Example I was suspended together with 1.1 molar equivalents of N-bromoacetamide in 35 cc. of anhydrous methylene chloride and added over 3 minutes with stirring to a mixture of 75 mol equivalents of anhydrous hydrogen fluoride and 18 g. of anhydrous tetrahydrofuran in a polyethylene bottle at 80 C. After one hour at this temperature, it was kept for another hour at 0 C. and then added cautiously to an excess of an icecold solution of sodium carbonate. Extraction with methylene chloride and crystallization from acetonehexane furnished 5a fluoro 10,8 brorno-17fi-acetoxyestran-3fi-ol.

4 Example IV Following exactly the same procedure described in Example IIII except that the hydrogen fluoride was substituted by hydrogen chloride, there was obtained 5achloro-lO/i-bromo-l7 8-acetoxy-estran-3li-ol.

Example V A suspension of 1 g. of l7fl-acetoxy-A -estren-Iafi-ol (obtained according to Example I) and 1.1 molar equivalents of N-iodo succinimide in 20 cc. of methylene chloride was added with stirring over 5 minutes to a mixture of 75 mol. equivalents of anhydrous hydrogen fluoride and 18 g. of anhydrous tetrahydrofuran at C. The operation was conducted in a polyethylene bottle. After 2 hours at 80 C. and 12 hours at 0 C. the mixture was added cautiously toan excess of sodium bicarbonate in ice-water. The product was extracted in the methylene chloride and the extract washed successively with water, sodium thiosulfate solutionand water, dried over sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane aflorded' Sa-fluoro-lOfl-iodo- 17fi-acetoxy-estran3/i-ol.

Example V1 1 g. of 17,8-acetoxy-A -estren-BB-ol (obtained according to Example I) was treated following exactly the same procedure described in Example V except that the hydrogen fluoride was substituted by hydrogen chloride and furnished 5oc-chloro-l0B-iodo-l7fi-acetoxy-estran- 33-01.

Example VII 1 g. of l7a-methyl-A -estren-l7fl-ol-3-one (F. B. Colton, US. Patent 2,905,676) was reduced exactly in the same way as described in Example I thus furnishing 17a-methyl-A -estrene-3;8,17,6-diol.

A solution of 0.75 g. of the foregoing steroid was brominated following the procedure described in Example I furnishing 5a,10 8-dibromo-17a-methyl-estran-3fi, 1713-diol.

Example VIII 1 g. of 17a-methyl-A -estrene-3B,l7B-diol (obtained according to Example VII) was chlorinated such as described in Example II yielding 5a,l0B-dichloro-17a-methyl-estrane-3;3,l7,6-diol.

Example IX Following the procedure described in Example III, the reaction of 17a-methyl-A -estrene-3;3,17/3-diol with the bromine fluoride (formed in situ from the N-bromoacetamide and hydrogen fluoride) furnished SOt-flUOI'O- 1OB-bromo-l7a-methyl-estrane-3fi,17/8-diol.

Example X Upon treatment of 17a-methyl-A -estrene-Elfi,17B- diol in the same way as described in Example IV, there was obtained SOL-ChIOIO-IOfl-bI'OIIlO-170C-In6thY1-6SII3I1C- 3,9,17,8-diol.

Example XI 1 g. of 17a-methyl-A -estrene-3;8,17B-diol was treated following exactly the procedure described in Example V thus furnishing Set-fluoro-lOfi-iodo-l7a-methyl-estrane-3fi, 17fi-diol.

Example XII 1 g. of 17a-methyl-A -estrene3B,17/3-diol was treated in accordance with the method described in Example VI, giving Sa-chIoro-IOfi-iodo-17u-methyl-estrane- 3,8,17/3-diol.

Example X111 1 g. of 17a-ethyl-A -estren-17fl-0l-3-one (F. B. Colton, US. Patent 2,905,676), was reduced with sodium borohydride, following exactly the procedure described in Example I, giving 17a-ethyl-A -estrene-3B,17fl-diol.

This steroid was brominatedsuch as described in the same example, thus affording 5a,10,8-dibrorno-17a-ethy1- estran-3p,17B-diol.

' Example XIV 1 g. of 17a-ethyl-A -estrene-3B,l7fi-diol obtained according to Example XIII was chlorinated following the technique disclosed in Example ll yielding 50,1Ofl-dichloro-l7a-ethyl-estrane-l3fl,17,8-diol.

. Example XV Following the procedure described in Example III, the reaction of 17a-ethyl-A -estrene-3fi,l7/3-diol with N- bromoacetamide and hydrogen fluoride, furnished 5ozfiuoro- 3-bromo-17a-ethyl-estran-3B,17B-dio1.

Example XVI Treating 1 g. of 17a-ethyl-A -estrene-3[3,17 3-diol such as described in Example IV, there was obtained 5achloro-10fl-bromo-17a-ethy1-estrane-3fi,17p-diol.

Example XVII 0.750 mg. of 17a-ethy1-A -estrene-3fl,17B-diol were treated following the technique described in Example V giving Son-fluoro-1OB-iodo-17a-ethyl-estrane-35,17fi-diol.

Example XVIII 1 g. of l7a-ethyl-A -estrene-3B,17/3-diol was treated in accordance with the method described in Example VI, giving 5a-ChlO10- IOfi-iodo-l7a-ethyl-estrane-175,3 fi-diol.

Example XIX 1 g. of l7a-ethynyl-A -estren-l75-01-3-one (F. B. Colton, US. Patent 2,725,389) was reduced with sodium borohydride such as described in Example I furnishing 17x-Btl1YI1Yl-A -6Str61163fi,17[3dl0l.

This steroid was brominated in exactly the same conditions as described in Example I thus affording 50:,10B-dibromo-l7a-ethynyl-estrane-3/3,17,8-diol.

Example XX 1 g. of 17a-ethynyl-A -estrene-llfi,l7fi-diol was chlorinated following the technique described in Example 11 yielding 5a,IOfi-dichloro-17ot-ethynyl-estrane-flt5,17p diol. I

Example XXI 1 g. of l7a-ethynyl-A -estrene-3 3,17fi-diol was treated in the same Way as described in Example Ill giving 5 a-fluoro-1OQ-bromo-17a-ethynyl estrane-3 6,17,8-diol.

Example XXII Upon treatment of 17a-ethynyl-A -estrene-3fi,17B- iol following the technique described in Example IV, there was obtained Sa-chIoro-lOfi-bromo-l7x-ethynylestrane-3[3,l7fl-diol.

Example XXIII Treating 1 g. of 17a-ethynyl-A -estrene-3B,17B-diol such as described in Example V, there was obtained 50:- fiuoro-10fi-iodo-17a-ethynyl-estrane-3B,17p-diol.

Example XXIV 1 g. of 17u-ethynyl-A estrene-3fi,17B-diol was treated in accordance with Example VI, thus yielding 5achloro-IOti-iodo-l7a-ethynyl-estrane-3p,17/3-diol. l

Example XXV 1 g. of 5oz,IOfi-dibromo-17oc-ethynyl-3/3,17/3-dio1 (obtained in accordance with Example XIX) dissolved in 50 cc. of pyridine and in the presence of 800 mg. of prehydrogenated 2% palladium on calcium carbonate catalyst was stirred under hydrogen at room temperature and atmospheric pressure. When 1 mol equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst filtered, washed with ethyl acetate, and the combined 7 solutions evaporated to dryness under vacuum. The crude product was recrystallized from acetone yielding 5a,10,8-dibrorno-l7a-ethenyl-estrane-3p,17fi-diol.

Treating exactly iri the same way the starting materials mentioned below, there were obtained the corresponding products indicated:

Starting material Product 5a, lOB-dlChlOlO-l'la-GtllGllYl-ES- gage-3B, 17341101 (Example tram-35, H S-diol.

estrane-Efl 17B-diol (Example XXII).

Example XXVI- estran-3 -one.

In accordance with the method described were treated the starting materials listed below, thus furnishing the corresponding products indicated:

Starting material Product 513, 1(1))?-diehlor0-17B-acetoxy-estran- 7 Example XX VII 1 g. of a,10,8-dibromo-l7a-methyl-estrane-3B,l75-diol in cc. of pyridine was treated with 2 cc. of acetic anhydride. The mixture was left overnight at room temperature, then it was poured into water and extracted with methylene chloride. The extract was washed successively with diluted chlorhydric acid, 5% sodium bicarbonate aqueous solution, and water to neutral, then dried and evaporated to dryness. Recrystallization of the solid residue from ethyl acetate-hexane afforded the 3,8-acetate of 5a,lOfi-dibromo-l7a-methyl-estrane-3fi,l7B-diol.

Following exactly the above technique were treated the starting compounds set forth below, thus yielding the indicated products:

Starting compound Product Example XX VIII Starting compound Product I claim: 1. A compound of the following formula:

fill

wherein A is selected from the group consisting of fi-hydroxymethylene and fi-hydrocarbon carboxylic acyloxymethylene of less than 12 carbon atoms; X is selected from the group consisting of chlorine, bromine and iodine; Y is selected from the group consisting of fluorine, chlorine and bromine; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an alkyl radical of up to 12 carbon atoms and when R is hydrogen, R is the hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

wherein A is selected from the group consisting of fl-hydroxymethylene and li-hydrocarbon carboxylic acyloxymethylene of less than 12 carbon atoms; X is selected from the group consisting of chlorine, bromine and iodine; Y is selected from the group consisting of fluorine, chlorine and bromine; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R is selected from the group consisting of an alkenyl and alkynyl radical containing up to 12 carbon atoms.

8. 5a chloro-lOfl-bromo-17a-ethynyl-estrane-3p,17,9- diol.

9. Sat-fluoro-1OB-iodo-17a-ethenyl-estrane-3/3,17,8-diol.

10. 50c fluoro-lOB-bromo-17a-ethynyl-estran-17/3-01-3- one.

11. 5a chloro IO/B-bromo-17a-ethenyl-estran-17,8-01- 3-one.

12. In a process for the production of 5a,10,B-dihaloestrane derivatives selected from the group consisting of 5a,10B-dihalo-17fl-hydroxy-estran-3-one, 50:,10fi dihalo- 35,17,8-dihydroxy estrane, the Una-aliphatic hydrocarbon derivatives and the hydrocarbon carboxylic acid esters thereof of up to 12 carbon atoms, the step which comprises treating the corresponding 3fl-ol-A -estrane derivative with a halogenating agent selected from the group consisting of chlorine, bromine fluoride, iodine fluoride, bromine chloride and iodine chloride in a suitable solvent selected from the group consisting of carbon tetrachloride and methylene chloride.

13. The process of claim 12 wherein the halogenating agent is chlorine and the solvent is carbon tetrachloride.

14. The process of claim 12 wherein the halogenating agent is bromine fluoride generated in situ from N- bromoacetarnide and hydrogen fluoride, and the solvent is methylene chloride.

15. The process of claim 12 wherein the halogenating agent is iodine fluoride generated in situ from N-iodo succinimide and hydrogen fluoride and the solvent is methylene chloride.

16. The process of claim 12 wherein the halogenating agent is bromine chloride generated in situ from N- bromoacetarnide and hydrogen chloride and the solvent is methylene chloride.

17. The process of claim 12 wherein the halogenating agent is iodine chloride generated in situ from N-iodo succinimide and hydrogen chloride, and the solvent is methylene chloride.

References Cited in the file of this patent Reimann et al.: I.A.C.S. 82, pp. 2308-2311, May 5, 1960.

Chem. and Eng. News, September 26, 1960, p. 56 (cols. 2-3). 

1. A COMPOUND OF THE FOLLOWING FORMULA: 